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Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors

Abstract

G proteins are key mediators of G protein-coupled receptor signalling, which facilitates a plethora of important physiological processes. The cyclic depsipeptides YM-254890 and FR900359 are the only known specific inhibitors of the Gq subfamily of G proteins; however, no synthetic route has been reported previously for these complex natural products and they are not easily isolated from natural sources. Here we report the first total synthesis of YM-254890 and FR900359, as well as of two known analogues, YM-385780 and YM-385781. The versatility of the synthetic approach also enabled the design and synthesis of ten analogues, which provided the first structure–activity relationship study for this class of compounds. Pharmacological characterization of all the compounds at Gq-, Gi- and Gs-mediated signalling provided succinct information on the structural requirements for inhibition, and demonstrated that both YM-254890 and FR900359 are highly potent inhibitors of Gq signalling, with FR900359 being the most potent. These natural products and their analogues represent unique tools for explorative studies of G protein inhibition.

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Figure 1: Structures and retrosynthetic analysis of YM-254890, FR900359 and analogues.
Figure 2: Chemical synthesis of YM-254890, FR900359 and analogues.
Figure 3: Pharmacological properties of the Gq inhibitors.

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Acknowledgements

We thank C. A. Olsen for constructive comments on the manuscript, and D. Stærk for performing the HRMS. H.B.-O. and K.S. acknowledge financial support from the Lundbeck Foundation. X.-F.X. thanks the Novo Nordisk Foundation, H.Z. thanks the Chinese Scholarship Council, C.R.U. acknowledges financial support from the Lundbeck Foundation, D.E.G. thanks the European Research Commission (DE-ORPHAN 639125) and the Lundbeck Foundation (R163-2013-16327), M.M. was supported by the National Institutes of Health (NIH) grant R01-DK100584, T.J.G. by NIH P01-DK11794, Project I, and M.M. and T.J.G. by the Center for Skeletal Research Core (NIH P30 AR066261).

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Authors

Contributions

H.B.-O. and K.S. conceived the project. X.-F.X., H.Z. and K.S. designed the synthesis, and X.-F.X. and H.Z. performed the synthesis. C.R.U. and M.F.W. performed pharmacological characterization. T.J.R. and M.M. performed the characterization of mutant G proteins. K.H. performed molecular modelling. K.S., H.B.-O., D.E.G. and M.M. supervised the research. X.-F.X. and K.S. wrote the manuscript, with input from all the authors.

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Correspondence to Kristian Strømgaard.

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Xiong, XF., Zhang, H., Underwood, C. et al. Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors. Nature Chem 8, 1035–1041 (2016). https://doi.org/10.1038/nchem.2577

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